Objective: The primary objective of this study was to compare the analgesic effects of intrathecal ropivacaine with or without neostigmine or dexmedetomidine in lower limb surgeries. Secondary objectives were to study the characteristics of block, duration of analgesia, postoperative analgesic requirement, and associated side effects. Materials and Methods: Seventy-five patients posted for elective orthopedic lower limb surgeries under spinal anesthesia were randomly divided into three equal groups to receive intrathecal ropivacaine 0.5% alone (Group R), with adjuvant 5 μg dexmedetomidine (Group R + D) or 50 μg neostigmine (Group R + N). Time to achieve T10 sensory block, time to 2-segment regression, duration of regression to L4, maximum modified Bromage score and duration of analgesia were noted. The incidences of adverse events such as nausea, vomiting, hypotension, bradycardia, desaturation, shivering, and itching were also noted. Statistical analysis was performed using two sample t-test for normally distributed variables and Pearson's Chi-squared test for categorical data. The level of significance was set as P < 0.05. Results: Quality of motor and sensory blockage was significantly better in both Group R + D and Group R + N than Group R. Mean time to achieve T10 sensory block was lowest, time taken in regression of block by 2-segments and duration of regression to L4 was longest in Group R + D and was significant when compared to other groups. Adverse effects such as nausea and vomiting were highest in Group R + N and was statistically significant as compared to other groups. Conclusions: Dexmedetomidine is a better intrathecal adjuvant emerged as compared to neostigmine due to faster onset of anesthesia, better intra- and post-operative analgesia and prolonged duration of motor and sensory blockade without significant increase in adverse effects.

Subarachnoid block is still the first choice for lower limb surgeries because of its rapid onset, superior blockade, low risk of infection as from catheter in situ, less failure rates, and cost-effectiveness, but has the drawback of shorter duration of the block and lack of postoperative analgesia. The duration and quality of spinal anesthesia can be increased by increasing the dose and concentration of local anesthetic but on the cost of local anesthetic systemic toxicity.

Ropivacaine is nearly identical to bupivacaine in onset, and quality of sensory block, has a better safety profile, but it produces lesser duration of motor blockade.[1] Thus ropivacaine is very useful for short duration surgeries as well as for early ambulation, but postoperative pain is an important concern.

In recent years, use of intrathecal adjuvant has gained popularity with the aim of prolonging the duration of block, better success rate, patient satisfaction, decreased resource utilization compared with general anesthesia and faster recovery. Hence, the aim was to find a drug as an adjuvant with ropivacaine which provides better intraoperative hemodynamic condition as well as prolonged postoperative analgesia with minimal side effects. Commonly opioids are used as adjuvants to local anesthetic, but they are associated with a number of undesirable side effects including delayed respiratory depression, urinary retention, pruritus, hemodynamic instability, nausea, and vomiting.[2]

Neostigmine is an anticholinesterase agent which increases the acetylcholine concentrations at cholinergic synapses. Spinal neostigmine apparently activates descending pain inhibitory systems that rely on a spinal cholinergic interneuron, probably exacerbating a cholinergic tonus that is already activated during the postoperative period [3],[4],[5],[6] and seems to be extremely efficient for alleviating somatic pain.

Dexmedetomidine is a more selective α2-adrenoceptor agonist and has recently been used as an adjuvant to intrathecal local anesthesia.[7],[8],[9] Gupta et al.[10] used 5 μg of dexmedetomidine with ropivacaine and found it to be associated with prolonged motor and sensory block, hemodynamic stability and reduced demand for rescue analgesics in 24 h as compared to fentanyl. Intrathecal α2-receptor agonists are found to have an antinociceptive action for both somatic and visceral pain.

The primary objective was to compare the analgesic effects of intrathecal ropivacaine with or without neostigmine or dexmedetomidine in lower limb surgeries. Secondary objectives were to study the characteristics of block, duration of analgesia, postoperative analgesic requirement, and associated side effects.

Materials and Methods

This prospective randomized controlled, double-blinded study was conducted on 75 patients from September 2015 to July 2016 with the approval of an ethical committee of the institution. A written and informed consent was obtained from all patients. Patients included for the study were the American Society of Anesthesiologists (ASA) physical status Class I or II, of either sex (18–60 years) presenting for elective lower limb surgeries. Patients who had contraindications to spinal anesthesia, allergy to the drug, were excluded from the study groups. All patients received a tablet of alprazolam 0.5 mg orally the night before surgery. On arrival in the operating room, intravenous (i.v.) access was secured with 18G cannula and patients were preloaded with ringer's lactate solution at 15 ml/kg. All patients were monitored with automated noninvasive blood pressure, pulse oxymetry, and electrocardiogram. Spinal needles used were 26 G pencil point needles and were introduced at L3–L4 interspace in sitting position with all aseptic precautions. Patients were allocated into three groups having 25 patients in each group. They were randomized on the basis of a sealed envelope technique to receive one of the following:

Injections were given over approximately 10–15 s. Immediately, after completion of the block, patients were made to the supine position. Oxygen was administrated through a mask if the pulse oximetry reading decreased below 92%. Hypotension was defined as a decrease in systolic blood pressure by more than 30% from baseline or <90 mmHg and was treated with incremental i.v. doses of mephentermine 3 mg and further boluses of i.v. fluid as required. Bradycardia was defined as heart rate (HR) <50 bpm was treated with i.v. atropine 0.6 mg if it was associated with hypotension. The incidence of adverse effects such as nausea, vomiting, shivering, itching, pruritus, respiratory depression, sedation, and hypotension was recorded. Sensory testing was assessed by loss of pinprick sensation to 23 G hypodermic needle and dermatome levels were tested every 2 min until the highest level had stabilized for four consecutive tests. Testing was then conducted every 10 min until the point of two segment regression of the block. Further testing was performed at 20 min intervals until the recovery of L4 dermatome. Anesthesiologist who performed the block and did an assessment of the block was different from one who prepared the drugs. The surgeons were blinded to the patient groups. Data regarding the time to reach T10 from the time of injection, time to 2-sensory regression and incidence of side effects were collected. Sedation score was assessed with a four-point verbal rating scale (1 = no sedation, 2 = light sedation, 3 = somnolence, 4 = deep sedation).

Intra- and post-operatively, pain scores were recorded using visual analog scale (VAS) between 0 and 10 (0 = no pain, 10 = the most severe pain), initially every 1 h for 2 h, then every 2 h for next 8 h and then after every 4 h till 24 h. Injection fentanyl 0.5 μg/kg i.v. was given intraoperatively as rescue analgesia when VAS ≥2. Follow-up was carried out 1 week postoperatively by the blinded anesthetist who asked about postoperative headache as well as postoperative pain and dysesthesias in the buttock, thighs, or lower limbs. Statistical analysis was done by statistical programming software Statistical Package for the Social Sciences (SPSS) Statistics version 23.0.0 (SPSS Inc., Chicago, Illinois, USA) for analyzing the collected data. Parametric data were reported as an arithmetic mean ± standard deviation and analyzed by using two sample t-test. The comparison of categorical data was studied using Pearson's Chi-squared test. P < 0.05 was considered statistically significant. Twenty-five patients per group were required to detect a significant difference of 25% or more in the requirement of rescue analgesia between the two groups (power of 85%, α = 0.05).

Results

The groups were comparable with respect to age, sex, height, weight, ASA physical status class, and duration of surgery [Table 1]. There was no significant difference in the type of surgery [Table 2].

The mean time to achieve T10 sensory block, time to 2-segment regression and duration of regression to L4 was significantly different among the groups. Mean time to achieve T10 sensory block was lowest in Group R + D and was significant when compared to other groups. Time taken in regression of block by 2-segments and duration of regression to L4 was longest in Group R + D and was significant when compared to other groups [Table 3].

Maximum modified Bromage score and Bromage score at 2 h was lowest in Group R + D and was significant as compared to other groups. Time to motor recovery was longest in Group R + D which was statistically significant when compared to other groups [Table 4].

None of the patients in Group R + D required fentanyl and midazolam as rescue analgesia and sedation in the intraoperative period. Fentanyl and midazolam requirement was highest in Group R and was significant as compared to Group R + N. Requirement of mephentermine and atropine was highest in Group R + D [Table 5]. Intra-operative VAS was minimum and sedation was maximum in Group R + D which was statistically significant as compared to other groups [Table 6]. Time to 1st analgesia requirement postoperatively was significantly delayed in both Group R + D and Group R + N as compared to Group R. Time to 1st analgesic requirement was longest in Group R + D and was also found to be significantly delayed as compared to Group R + N. However, total dose of Tramadol used in the 24 h postoperative period did not differ among the groups [Table 7].

Adverse effects such as bradycardia and hypotension were highest in Group R + D but not statistically significant. Nausea and vomiting were highest in Group R + N and was statistically significant as compared to other groups [Table 8].

Ropivacaine is now seen as an alternative to bupivacaine because of its less toxic effect on the central nervous system and cardiovascular system and rapid recovery of motor function. In the previous studies [11],[12] intrathecal injection of plain ropivacaine produced a sensory block of variable extent and considerable number of patients required general anesthesia to accomplish surgery. Hyperbaric ropivacaine produces more predictable and reliable sensory and motor block, with faster onset than a plain solution.[13],[14] As hyperbaric ropivacaine is not available commercially, various adjuvants are studied to increase its sensory block and decrease its disadvantages.

Alpha-2 adrenergic agonistic action of dexmedetomidine has a synergistic effect on local anesthetics through prolongation of the sensory block by depressing neurotransmitter release from C-fibers of the spinal cord leading to hyperpolarization of postsynaptic dorsal horn neurons.[15] Motor block prolongation also occurs in conjunction by binding of α2 agonists to motor neuron in the dorsal horn of spinal cord. Dexmedetomidine has been used intrathecally in varying doses ranging from 3 to 15 μg.[8],[16],[17],[18],[19] The optimal dose of intrathecal dexmedetomidine has not been established. Sullivan et al.[20] have found in their study that ED50 of dexmedetomidine for inhibition of C fiber responses of dorsal horn neurons was 2.5 μg and β-evoked responses were inhibited to a lesser degree with a maximum inhibition seen above 10 μg dose. Hence, in this study, a low dose of 5 μg (more than ED50) was used to provide adequate postoperative analgesia, limit the motor blockade and facilitate early recovery and ambulation.

It is speculated that neostigmine being a cholinesterase inhibitor increases the spinal level of acetylcholine. Acetylcholine at a spinal level may augment the motor blockage as a result of axonal conduction block from the local anesthetic. Spinal neostigmine is advantageous over other currently used spinal drugs as it causes no hypotension, no sedation, no respiratory depression or neurological dysfunction.[4],[21] Most of the studies have used neostigmine with bupivacaine. Our study was unique in using neostigmine with ropivacaine which has better safety profile as compared to bupivacaine. It was postulated that neostigmine as an adjuvant to ropivacaine will augment its motor and sensory blockage. Doses ranging from 6.25 to 150 μg of intrathecal neostigmine have been used in previous studies.[4],[21],[22],[23],[24],[25] Most of the studies [22],[23],[24] have found 50 μg of neostigmine as the adequate dose for intrathecal use as increasing the dose causes increase in side effects such as nausea and vomiting.

Thus, our study was designed to evaluate a better adjuvant to ropivacaine for lower limb surgeries.

The addition of dexmedetomidine or neostigmine both significantly decreased the time to reach sensory blockage and increased the duration of the block as compared to plain intrathecal ropivacaine. However, dexmedetomidine was significantly better in both early onset and long duration of the block as compared to neostigmine. Mean time to reach sensory T10 level was 5.42 min with 5 μg dexmedetomidine which was similar to findings of Naithani et al.[26]

Liu et al.[22] and Pan et al.[27] demonstrated prolonged durations of sensory block with 50 μg of neostigmine with intrathecal bupivacaine in their studies which had similar findings as ours studies.

Both dexmedetomidine and neostigmine when added as an adjuvant to intrathecal ropivacaine increased the quality and duration of motor blockage. Dexmedetomidine significantly produced better motor blockage and increased the duration of motor blockage as compared to neostigmine. Liu et al.,[22] Pan et al.,[27] and Tan et al.[28] have also found a significantly prolonged motor block with a similar dose of neostigmine. Intrathecal neostigmine causes motor block by acetylcholine-mediated reduction in motor neuron outflow with no reduction in spinal cord blood flow or histopathological changes.[29]

VAS was minimum and sedation was maximum with dexmedetomidine which was significant as compared to other group. None of the patients in this group required rescue analgesic or sedation intraoperatively. This was due to better and long lasting sensory and motor blockage. Time to first analgesic requirement postoperatively was approximately 6 h in both dexmedetomidine and neostigmine as compared to 4 h in plain ropivacaine group.

Al-Ghanem et al.[7] have reported the use of dexmedetomidine to be associated with a decrease in HR and blood pressure. In the present study, incidence of side effects such as hypotension and bradycardia were more common with both dexmedetomidine and neostigmine but was statistically nonsignificant. The reason could be a combination of dexmedetomidine with ropivacaine which is a better drug in terms of cardiovascular and hemodynamic control.

Intrathecal neostigmine is associated with nausea and vomiting which is dose-dependent, severe and minimum at doses <5 μg.[30] Nausea associated with spinal neostigmine is thought to result from the spread in cerebrospinal fluid to brainstem sites. Ho et al.[31] in a meta-analysis aimed to evaluate the effectiveness and side-effects of intrathecal neostigmine in the perioperative and peripartum settings found that it is associated with significant side-effects and the disadvantages outweigh the minor improvement in analgesia achieved. Our study have also found incidence of nausea and vomiting in more than 40% of the patients making it difficult to use routinely despite better quality and duration of block characteristics.

Conclusions

In this study, dexmedetomidine emerged as a superior drug when compared to neostigmine as an adjunct with intrathecal ropivacaine 0.5% for patients undergoing lower limb surgery because it provides faster onset of anesthesia, better intra- and post-operative analgesia and prolonged duration of motor and sensory blockade without a significant increase in adverse effects. Neostigmine in the dose of 50 μg intrathecally produces a better quality of block but with a higher incidence of side effects. Therefore, we encourage a formal study to determine an optimal dose of intrathecal neostigmine which is devoid of side effects.